̽��ֱ�� of Cambridge - Metabolic Research Laboratories

Map of brain’s appetite centre could enable new treatments for obesity and diabetes

Anonymous — Wed, 05 Feb 2025 16:00:15 +0000

Published today in Nature, this comprehensive resource, called HYPOMAP, provides an unparalleled view of the brain’s appetite centre and promises to accelerate the development of treatments for obesity and type 2 diabetes.

̽��ֱ��hypothalamus is often described as the brain’s ‘control centre’, orchestrating many of the body’s most vital processes. While much of our knowledge of the hypothalamus comes from animal studies, especially in mice, translating these findings to humans has long been a challenge. HYPOMAP bridges this gap by providing an atlas of the individual cells within the human hypothalamus. This resource not only charts over 450 unique cell types but also highlights key differences between the human and mouse hypothalamus — differences that have major implications for drug development.

“This is a game-changer for understanding the human hypothalamus,” said Professor Giles Yeo, senior author of the study from the Institute of Metabolic Science-Metabolic Research Laboratories (IMS-MRL) and MRC Metabolic Diseases Unit, ̽��ֱ�� of Cambridge.

“HYPOMAP confirms the critical role of the hypothalamus in body-weight regulation and has already allowed us to identify new genes linked to obesity. It gives us a roadmap to develop more effective, human-specific therapies.”

Together with researchers at the Max Planck Institute for Metabolism Research in Cologne, Professor Yeo and colleagues used cutting-edge technologies to analyse over 400,000 cells from 18 human donors. HYPOMAP allows researchers to pinpoint specific cell types, understand their genetic profiles, and explore how they interact with neighbouring cells. This detailed cellular resolution offers invaluable insights into the circuits that regulate appetite and energy balance, as well as other functions such as sleep and stress responses.

Comparison with a mouse hypothalamus atlas revealed both similarities and critical differences. Notably, some neurons in the mouse hypothalamus have receptors for GLP-1 — targets of popular weight-loss drugs like semaglutide — that are absent in humans.

"While drugs like semaglutide have shown success in treating obesity, newer therapies target multiple receptors such as GLP-1R and GIPR. Understanding how these receptors function specifically in the human hypothalamus is now crucial for designing safer and more effective treatments," said Dr Georgina Dowsett from the Max Planck Institute for Metabolism Research and formerly at the IMS-MRL.

“Our map of the human hypothalamus is an essential tool for basic and translational research,” added Professor Jens C. Brüning, Director at the Max Planck Institute. “It allows us to pinpoint which mouse nerve cells are most comparable to human cells, enabling more targeted preclinical studies.”

HYPOMAP’s open-access nature ensures that it will be an invaluable resource for scientists worldwide. By offering insights into the hypothalamus’s role in conditions ranging from obesity to cachexia (a wasting condition associated with several illness, which involves extreme loss of muscle and fat), it provides a foundation for tackling some of the most pressing health challenges of our time.

Dr John Tadross, Consultant Pathologist at Addenbrooke’s Hospital and lead author from IMS-MRL, said: “This is just the beginning. ̽��ֱ��atlas itself is a milestone, but what could really make a difference for patients is understanding how the hypothalamus changes in people who are overweight or underweight. This could fundamentally shift our approach to metabolic health and enable more personalised therapies.”

With HYPOMAP, researchers have a new tool to unlock the secrets of the human brain’s metabolic control centre. By better understanding the human hypothalamus, science takes a significant step toward combating obesity, type 2 diabetes, and related conditions.

Reference
Tadross, JA, Steuernagel, L & Dowsett, GKC et al. A comprehensive spatio-cellular map of the human hypothalamus. Nature; 5 Feb 2025; DOI: 10.1038/s41586-024-08504-8

Adapted from a story by the Institute of Metabolic Science-Metabolic Research Laboratories and the Max Planck Institute for Metabolism Research

Scientists have created the most detailed map to date of the human hypothalamus, a crucial brain region that regulates body weight, appetite, sleep, and stress.

HYPOMAP confirms the critical role of the hypothalamus in body-weight regulation and has already allowed us to identify new genes linked to obesity

Giles Yeo

Sander Dalhuisen

Person holding burger bun with vegetables and meat

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Genetic study points to oxytocin as possible treatment for obesity and postnatal depression

cjb250 — Tue, 02 Jul 2024 15:00:18 +0000

Obesity and postnatal depression are significant global health problems. Postnatal depression affects more than one in 10 women within a year of giving birth and is linked to an increased risk of suicide, which accounts for as many as one in five maternal deaths in high income countries. Meanwhile, obesity has more than doubled in adults since 1990 and quadrupled in adolescents, according to the World Health Organization.

While investigating two boys from different families with severe obesity, anxiety, autism, and behavioural problems triggered by sounds or smells, a team led by scientists at the ̽��ֱ�� of Cambridge, UK, and Baylor College of Medicine, Houston, USA, discovered that the boys were missing a single gene, known as TRPC5, which sits on the X chromosome.

Further investigation revealed that both boys inherited the gene deletion from their mothers, who were missing the gene on one of their X chromosomes. ̽��ֱ��mothers also had obesity, but in addition had experienced postnatal depression.

To test if it was the TRPC5 gene that was causing the problems in the boys and their mothers, the researchers turned to animal models, genetically-engineering mice with a defective version of the gene (Trpc5 in mice).

Male mice with this defective gene displayed the same problems as the boys, including weight gain, anxiety, a dislike of social interactions, and aggressive behaviour. Female mice displayed the same behaviours, but when they became mothers, they also displayed depressive behaviour and impaired maternal care. Interestingly, male mice and female mice who were not mothers but carried the mutation did not show depression-like behaviour.

Dr Yong Xu, Associate Director for Basic Sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine, said: “What we saw in those mice was quite remarkable. They displayed very similar behaviours to those seen in people missing the TRPC5 gene, which in mothers included signs of depression and a difficulty caring for their babies. This shows us that this gene is causing these behaviours.”

TRPC5 is one of a family of genes that are involved in detecting sensory signals, such as heat, taste and touch. This particular gene acts on a pathway in the hypothalamus region of the brain, where it is known to control appetite.

When the researchers looked in more detail at this brain region, they discovered that TRPC5 acts on oxytocin neurons – nerve cells that produce the hormone oxytocin, often nicknamed the ‘love hormone’ because of its release in response to displays of affection, emotion and bonding.

Deleting the gene from these oxytocin neurons led to otherwise healthy mice showing similar signs of anxiety, overeating and impaired sociability, and, in the case of mothers, postnatal depression. Restoring the gene in these neurons reduced body weight and symptoms of anxiety and postnatal depression.

In addition to acting on oxytocin neurons, the team showed that TRPC5 also acts on so-called POMC neurons, which have been known for some time to play an important role in regulating weight. Children in whom the POMC gene is not working properly often have an insatiable appetite and gain weight from an early age.

Professor Sadaf Farooqi from the Institute of Metabolic Science at the ̽��ֱ�� of Cambridge said: “There's a reason why people lacking TRPC5 develop all of these conditions. We’ve known for a long time that the hypothalamus plays a key role in regulating ‘instinctive behaviours’ – which enable humans and animals to survive – such as looking for food, social interaction, the flight or fight response, and caring for their infants. Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a critical role in regulating our instincts.”

While deletions of the TRPC5 gene are rare, an analysis of DNA samples from around 500,000 individuals in UK Biobank revealed 369 people – around three-quarters of whom were women – that carried variants of the gene and had a higher-than-average body mass index.

̽��ֱ��researchers say their findings suggests that restoring oxytocin could help treat people with missing or defective TRPC5 genes, and potentially mothers experiencing postnatal depression.

Professor Farooqi said: “While some genetic conditions such as TRPC5 deficiency are very rare, they teach us important lessons about how the body works. In this instance, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite many decades of research. And importantly, it may point to oxytocin as a possible treatment for some mothers with this condition.”

There is already evidence in animals that the oxytocin system is involved in both depression and in maternal care and there have been small trials into the use of oxytocin as a treatment. ̽��ֱ��team say their work provides direct proof of oxytocin’s role, which will be crucial in supporting bigger, multi-centre trials.

Professor Farooqi added: “This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology, whether that’s our eating behaviour, anxiety or postnatal depression. We need to be more understanding and sympathetic towards people who suffer with these conditions.”

This work was supported by Wellcome, the National Institute for Health and Care Research (NIHR), NIHR Cambridge Biomedical Research Centre, Botnar Fondation and Bernard Wolfe Health Neuroscience Endowment.

Reference
Li, Y, Cacciottolo, TM & Yin, N. Loss of Transient Receptor Potential Channel 5 Causes Obesity and Postpartum Depression. Cell; 2 July 2024; DOI: 10.1016/j.cell.2024.06.001

Scientists have identified a gene which, when missing or impaired, can cause obesity, behavioural problems and, in mothers, postnatal depression. ̽��ֱ��discovery, reported on 2 July in Cell, may have wider implications for the treatment of postnatal depression, with a study in mice suggesting that oxytocin may alleviate symptoms.

This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology. We need to be more understanding and sympathetic towards people who suffer with these conditions

Sadaf Farooqi

Olli Turho (Getty Images)

Illustration of a tired African American mother crying

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Exercising during pregnancy normalises eating behaviours in offspring from obese mice

Anonymous — Tue, 04 Jun 2024 18:00:43 +0000

Previous studies in both humans and animal models have shown that the offspring of mothers living with obesity have a higher risk of developing obesity and type 2 diabetes themselves when they grow up. While this relationship is likely to be the result of a complex relationship between genetics and environment, emerging evidence has implicated that maternal obesity in pregnancy can disrupt the baby’s hypothalamus—the region of the brain responsible for controlling food intake and energy regulation.

In animal models, offspring exposed to overnutrition during key periods of development eat more when they grow up, but little is known about the molecular mechanisms that lead to these changes in eating behaviour.

In a study published today in PLOS Biology, researchers from the Institute of Metabolic Science and the MRC Metabolic Diseases Unit at the ̽��ֱ�� of Cambridge found that mice born from obese mothers had higher levels of the microRNA miR-505-5p in their hypothalamus—from as early as the fetal stage into adulthood. ̽��ֱ��offspring of obese mothers chose to eat more specifically of foods that were high in fat, which is consistent with fat sensing being disrupted in the hypothalamus.

Dr Laura Dearden from the Institute of Metabolic Science, the study’s first author, said: “Our results show that obesity during pregnancy causes changes to the baby's brain that makes them eat more high fat food in adulthood and more likely to develop obesity.”

Senior author Professor Susan Ozanne from the MRC Metabolic Diseases Unit and Institute of Metabolic Science said: “Importantly, we showed that moderate exercise, without weight loss, during pregnancies complicated by obesity prevented the changes to the baby's brain.”

Cell culture experiments showed that miR-505-5p levels can be influenced by exposing hypothalamic neurons to long-chain fatty acids and insulin, which are both high in pregnancies complicated by obesity. ̽��ֱ��researchers identified miR-505-5p as a regulator of pathways involved in fatty acid uptake and metabolism – high levels of the miRNA make the offspring brain unable to sense when they are eating high fat foods. Several of the genes that miR-505-5p regulates are associated with high body mass index in human genetic studies, showing these same changes in humans can cause obesity.

̽��ֱ��study is one of the first to demonstrate the molecular mechanisms linking nutritional exposure in utero to eating behaviour.

Dr Dearden added: “While our work was only carried out in mice, it may help us understand why the children of mothers living with obesity are more likely to become obese themselves, with early life exposures, genetics and current environment all being contributing factors.”

Reference
Dearden, L et al. Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food. PLOS Biology; 4 Jun 2024; DOI: 10.1371/journal.pbio.3002641

Adapted from a press release by PLOS Biology

Maternal obesity in pregnancy changes the eating behaviours of offspring by increasing long-term levels of particular molecules known as microRNAs in the part of the brain that controls appetite – but this can be changed by exercise during pregnancy, a study in obese mice has suggested.

We showed that moderate exercise, without weight loss, during pregnancies complicated by obesity prevented the changes to the baby's brain

Susan Ozanne

Engin_Akyurt (Pixabay)

Fast food meal of burger and fries

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Genetic mutation in a quarter of all Labradors hard-wires them for obesity

jg533 — Wed, 06 Mar 2024 19:06:36 +0000

This obesity-driving combination means that dog owners must be particularly strict with feeding and exercising their Labradors to keep them slim.

̽��ֱ��mutation is in a gene called POMC, which plays a critical role in hunger and energy use.

Around 25% of Labradors and 66% of flatcoated retriever dogs have the POMC mutation, which researchers previously showed causes increased interest in food and risk of obesity.

̽��ֱ��new study reveals how the mutation profoundly changes the way Labradors and flatcoated retrievers behave around food. It found that although they don’t need to eat more to feel full, they are hungrier in between meals.

In addition, dogs with the POMC mutation were found to use around 25% less energy at rest than dogs without it, meaning they don’t need to consume as many calories to maintain a healthy body weight.

“We found that a mutation in the POMC gene seems to make dogs hungrier. Affected dogs tend to overeat because they get hungry between meals more quickly than dogs without the mutation,” said Dr Eleanor Raffan, a researcher in the ̽��ֱ�� of Cambridge’s Department of Physiology, Development and Neuroscience who led the study.

She added: “All owners of Labradors and flatcoated retrievers need to watch what they’re feeding these highly food-motivated dogs, to keep them a healthy weight. But dogs with this genetic mutation face a double whammy: they not only want to eat more, but also need fewer calories because they’re not burning them off as fast.”

̽��ֱ��POMC mutation was found to alter a pathway in the dogs’ brains associated with body weight regulation. ̽��ֱ��mutation triggers a starvation signal that tells their body to increase food intake and conserve energy, despite this being unnecessary.

̽��ֱ��results are published today in the journal Science Advances.

Raffan said: “People are often rude about the owners of fat dogs, blaming them for not properly managing their dogs’ diet and exercise. But we’ve shown that Labradors with this genetic mutation are looking for food all the time, trying to increase their energy intake. It’s very difficult to keep these dogs slim, but it can be done.”

̽��ֱ��researchers say owners can keep their retrievers distracted from this constant hunger by spreading out each daily food ration, for example by using puzzle feeders or scattering the food around the garden so it takes longer to eat.

In the study, 87 adult pet Labrador dogs - all a healthy weight or moderately overweight - took part in several tests including the ‘sausage in a box’ test.

First, the dogs were given a can of dogfood every 20 minutes until they chose not to eat any more. All ate huge amounts of food, but the dogs with the POMC mutation didn’t eat more than those without it. This showed that they all feel full with a similar amount of food.

Next, on a different day, the dogs were fed a standard amount of breakfast. Exactly three hours later they were offered a sausage in a box and their behaviour was recorded. ̽��ֱ��box was made of clear plastic with a perforated lid, so the dogs could see and smell the sausage, but couldn’t eat it.

̽��ֱ��researchers found that dogs with the POMC mutation tried significantly harder to get the sausage from the box than dogs without it, indicating greater hunger.

̽��ֱ��dogs were then allowed to sleep in a special chamber that measured the gases they breathed out. This revealed that dogs with the POMC mutation burn around 25% fewer calories than dogs without it.

̽��ֱ��POMC gene and the brain pathway it affects are similar in dogs and humans. ̽��ֱ��new findings are consistent with reports of extreme hunger in humans with POMC mutations, who tend to become obese at an early age and develop a host of clinical problems as a result.

Drugs currently in development for human obesity, underactive sexual desire and certain skin conditions target this brain pathway, so understanding it fully is important.

A mutation in the POMC gene in dogs prevents production of two chemical messengers in the dog brain, beta-melanocyte stimulating hormone (β-MSH) and beta-endorphin, but does not affect production of a third, alpha-melanocyte stimulating hormone (α-MSH).

Further laboratory studies by the team suggest that β-MSH and beta-endorphin are important in determining hunger and moderating energy use, and their role is independent of the presence of α-MSH. This challenges the previous belief, based on research in rats, that early onset human obesity due to POMC mutations is caused only by a lack of α-MSH. Rats don’t produce beta-melanocyte stimulating hormone, but humans and dogs produce both α- and β-MSH.

̽��ֱ��research was funded by ̽��ֱ��Dogs Trust and Wellcome.

Reference: Dittmann, M T et al: ‘Low resting metabolic rate and increased hunger due to β-MSH and β-endorphin deletion in a canine model.’ Science Advances, March 2024. DOI: 10.1126/sciadv.adj3823

New research finds around a quarter of Labrador retriever dogs face a double-whammy of feeling hungry all the time and burning fewer calories due to a genetic mutation.

Labradors with this genetic mutation are looking for food all the time, trying to increase their energy intake. It’s very difficult to keep these dogs slim, but it can be done.

Eleanor Raffan

A quarter of Labradors are hard-wired for obesity

Jane Goodall

Labrador retriever dog

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“Incredible” diabetes management app now recommended by NICE

cg605 — Tue, 07 Nov 2023 16:22:48 +0000

̽��ֱ��National Institute for Health and Care Excellence (NICE) has today (7 November 2023) recommended hybrid closed loop systems including the CamAPS FX app for use in managing type 1 diabetes, meaning that even more people living with the disease will be able to use this life-changing app.

DNA discovery highlights how we maintain healthy blood sugar levels after meals

cjb250 — Thu, 08 Jun 2023 15:00:48 +0000

̽��ֱ��findings, published today in Nature Genetics, could help inform future treatments of type 2 diabetes, which affects around 4 million people in the UK and over 460 million people worldwide.

Several factors contribute to an increased risk of type 2 diabetes, such as older age, being overweight or having obesity, physical inactivity, and genetic predisposition. If untreated, type 2 diabetes can lead to complications, including eye and foot problems, nerve damage, and increased risk of heart attack and stroke.

A key player in the development of the condition is insulin, a hormone that regulates blood sugar – glucose – levels. People who have type 2 diabetes are unable to correctly regulate their glucose levels, either because they don’t secrete enough insulin when glucose levels increase, for example after eating a meal, or because their cells are less sensitive to insulin, a phenomenon known as ‘insulin resistance’.

Most studies to date of insulin resistance have focused on the fasting state – that is, several hours after a meal – when insulin is largely acting on the liver. But we spend most of our time in the fed state, when insulin acts on our muscle and fat tissues.

It’s thought that the molecular mechanisms underlying insulin resistance after a so-called ‘glucose challenge’ – a sugary drink, or a meal, for example – play a key role in the development of type 2 diabetes. Yet these mechanisms are poorly-understood.

Professor Sir Stephen O’Rahilly, Co-Director of the Wellcome-MRC Institute of Metabolic Science at the ̽��ֱ�� of Cambridge, said: “We know there are some people with specific rare genetic disorders in whom insulin works completely normally in the fasting state, where it’s acting mostly on the liver, but very poorly after a meal, when it’s acting mostly on muscle and fat. What has not been clear is whether this sort of problem occurs more commonly in the wider population, and whether it’s relevant to the risk of getting type 2 diabetes.”

To examine these mechanisms, an international team of scientists used genetic data from 28 studies, encompassing more than 55,000 participants (none of whom had type 2 diabetes), to look for key genetic variants that influenced insulin levels measured two hours after a sugary drink.

̽��ֱ��team identified new 10 loci – regions of the genome – associated with insulin resistance after the sugary drink. Eight of these regions were also shared with a higher risk of type 2 diabetes, highlighting their importance.

One of these newly-identified loci was located within the gene that codes for GLUT4, the critical protein responsible for taking up glucose from the blood into cells after eating. This locus was associated with a reduced amount of GLUT4 in muscle tissue.

To look for additional genes that may play a role in glucose regulation, the researchers turned to cell lines taken from mice to study specific genes in and around these loci. This led to the discovery of 14 genes that played a significant role in GLUT 4 trafficking and glucose uptake – with nine of these never previously linked to insulin regulation.

Further experiments showed that these genes influenced how much GLUT4 was found on the surface of the cells, likely by altering the ability of the protein to move from inside the cell to its surface. ̽��ֱ��less GLUT4 that makes its way to the surface of the cell, the poorer the cell’s ability to remove glucose from the blood.

Dr Alice Williamson, who carried out the work while a PhD student at the Wellcome-MRC Institute of Metabolic Science, said: “What’s exciting about this is that it shows how we can go from large scale genetic studies to understanding fundamental mechanisms of how our bodies work – and in particular how, when these mechanisms go wrong, they can lead to common diseases such as type 2 diabetes.”

Given that problems regulating blood glucose after a meal can be an early sign of increased type 2 diabetes risk, the researchers are hopeful that the discovery of the mechanisms involved could lead to new treatments in future.

Professor Claudia Langenberg, Director of the Precision Healthcare ̽��ֱ�� Research Institute (PHURI) at Queen Mary ̽��ֱ�� of London and Professor of Computational Medicine at the Berlin Institute of Health, Germany, said: “Our findings open up a potential new avenue for the development of treatments to stop the development of type 2 diabetes. It also shows how genetic studies of dynamic challenge tests can provide important insights that would otherwise remain hidden.”

̽��ֱ��research was supported by Wellcome, the Medical Research Council and the National Institute for Health and Care Research.

Reference
Williamson, A et al. Genome-wide association study and functional characterisation identifies candidate genes for insulin-stimulated glucose uptake. Nat Gen; 8 June 2023; DOI: 10.1038/s41588-023-01408-9

A study of the DNA of more than 55,000 people worldwide has shed light on how we maintain healthy blood sugar levels after we have eaten, with implications for our understanding of how the process goes wrong in type 2 diabetes.

What’s exciting about this is that it shows how we can go from large scale genetic studies to understanding fundamental mechanisms of how our bodies work

Alice Williamson

eak_kkk (Pixabay)

Cola

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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‘Battle of the sexes’ begins in womb as father and mother’s genes tussle over nutrition

cjb250 — Mon, 27 Dec 2021 16:00:07 +0000

As the fetus grows, it needs to communicate its increasing needs for food to the mother. It receives its nourishment via blood vessels in the placenta, a specialised organ that contains cells from both baby and mother.

Between 10% and 15% of babies grow poorly in the womb, often showing reduced growth of blood vessels in the placenta. In humans, these blood vessels expand dramatically between mid and late gestation, reaching a total length of approximately 320 kilometres at term.

In a study published today in Developmental Cell, a team led by scientists at the ̽��ֱ�� of Cambridge used genetically engineered mice to show how the fetus produces a signal to encourage growth of blood vessels within the placenta. This signal also causes modifications to other cells of the placenta to allow for more nutrients from the mother to go through to the fetus.

Dr Ionel Sandovici, the paper’s first author, said: “As it grows in the womb, the fetus needs food from its mum, and healthy blood vessels in the placenta are essential to help it get the correct amount of nutrients it needs.

“We’ve identified one way that the fetus uses to communicate with the placenta to prompt the correct expansion of these blood vessels. When this communication breaks down, the blood vessels don’t develop properly and the baby will struggle to get all the food it needs.”

̽��ֱ��team found that the fetus sends a signal known as IGF2 that reaches the placenta through the umbilical cord. In humans, levels of IGF2 in the umbilical cord progressively increase between 29 weeks of gestation and term: too much IGF2 is associated with too much growth, while not enough IGF2 is associated with too little growth. Babies that are too large or too small are more likely to suffer or even die at birth, and have a higher risk to develop diabetes and heart problems as adults.

Dr Sandovici added: “We’ve known for some time that IGF2 promotes the growth of the organs where it is produced. In this study, we’ve shown that IGF2 also acts like a classical hormone – it’s produced by the fetus, goes into the fetal blood, through the umbilical cord and to the placenta, where it acts.”

Particularly interesting is what their findings reveal about the tussle taking place in the womb.

In mice, the response to IGF2 in the blood vessels of the placenta is mediated by another protein, called IGF2R. ̽��ֱ��two genes that produce IGF2 and IGF2R are ‘imprinted’ – a process by which molecular switches on the genes identify their parental origin and can turn the genes on or off. In this case, only the copy of the igf2 gene inherited from the father is active, while only the copy of igf2r inherited from the mother is active.

Lead author Dr Miguel Constância, said: “One theory about imprinted genes is that paternally-expressed genes are greedy and selfish. They want to extract the most resources as possible from the mother. But maternally-expressed genes act as countermeasures to balance these demands.”

“In our study, the father’s gene drives the fetus’s demands for larger blood vessels and more nutrients, while the mother’s gene in the placenta tries to control how much nourishment she provides. There’s a tug-of-war taking place, a battle of the sexes at the level of the genome.”

̽��ֱ��team say their findings will allow a better understanding of how the fetus, placenta and mother communicate with each other during pregnancy. This in turn could lead to ways of measuring levels of IGF2 in the fetus and finding ways to use medication to normalise these levels or promote normal development of placental vasculature.

̽��ֱ��researchers used mice, as it is possible to manipulate their genes to mimic different developmental conditions. This enables them to study in detail the different mechanisms taking place. ̽��ֱ��physiology and biology of mice have many similarities with those of humans, allowing researchers to model human pregnancy, in order to understand it better.

̽��ֱ��lead researchers are based at the Department of Obstetrics and Gynaecology, the Medical Research Council Metabolic Diseases Unit, part of the Wellcome-MRC Institute of Metabolic Science, and the Centre for Trophoblast Research, all at the ̽��ֱ�� of Cambridge.

̽��ֱ��research was largely funded by the Biotechnology and Biological Sciences Research Council, Medical Research Council, Wellcome Trust and Centre for Trophoblast Research.

Reference
Sandovici, I et al. ̽��ֱ��Imprinted Igf2-Igf2r Axis is Critical for Matching Placental Microvasculature Expansion to Fetal Growth. Developmental Cell; 10 Jan 2022: DOI: 10.1016/j.devcel.2021.12.005

Cambridge scientists have identified a key signal that the fetus uses to control its supply of nutrients from the placenta in a tug-of-war between genes inherited from the father and from the mother. ̽��ֱ��study, carried out in mice, could help explain why some babies grow poorly in the womb.

̽��ֱ��father’s gene drives the fetus’s demands for larger blood vessels and more nutrients, while the mother’s gene in the placenta tries to control how much nourishment she provides

Miguel Constância

Ionel Sandovici

Section of mouse fetus and placenta

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Many of us could carry up to 17kg of fat due to a change in a single gene

Anonymous — Thu, 27 May 2021 15:00:14 +0000

̽��ֱ��study led by scientists at the MRC Metabolic Diseases Unit which is part of the Wellcome-MRC Institute of Metabolic Science at the ̽��ֱ�� of Cambridge and the MRC Integrative Epidemiology Unit at the ̽��ֱ�� of Bristol is published today in Nature Medicine.

It has been known for a long time that obesity tends to run in families, but it was not until about 20 years ago that scientists started to discover that changes in specific genes can have very large effects on our weight even from early childhood.

One of these genes, the Melanocortin 4 Receptor (MC4R), makes a protein that is produced in the brain where it sends signals to our appetite centres, telling them how much fat we have stored. When the MC4R gene does not work properly, our brains think we have lower fat stores than we do, signalling that we are starving and need to eat.

̽��ֱ��research team found that around one in every 340 people may carry a disruptive mutation at MC4R. People who carry these mutations were more likely to have a greater weight from early childhood and, by 18 years of age, they were on average 17 kg (37 lbs or 2.5 stone) heavier, with the majority of this excess weight likely to be fat.

These results were found by studying the MC4R gene in a random sample of around 6,000 participants born in Bristol in 1990-91, who were recruited to Children of the 90s, a health study based at the ̽��ֱ�� of Bristol. This is a unique UK study that recruited approximately 80 percent of the births occurring in a specific region of the South West and which has continued to follow participants. As the Children of the 90s study managed to recruit such a high percentage of mothers during pregnancy, it is one of the most representative and comprehensive studies of its kind.

̽��ֱ��authors examined the MC4R gene in all 6,000 people and, whenever a mutation was found, went on to study its functional effects in the laboratory. This meticulous approach has provided the best estimates so far of the frequency and impact of MC4R mutations on people’s weight and body fat. Based on the frequency of mutations in this study, it is possible that around 200,000 people in the UK could carry a substantial amount of additional fat because of mutations in MC4R.

Professor Sir Stephen O’Rahilly, from the ̽��ֱ�� of Cambridge and one of the authors of the study, said: “Parents of obese children are often blamed for poor parenting and not all children obtain appropriate professional help. Our findings show that weight gain in childhood due to a single gene disorder is not uncommon. This should encourage a more compassionate and rational approach to overweight children and their families – including genetic analysis in all seriously obese children.”

Dr Kaitlin Wade, from the ̽��ֱ�� of Bristol’s MRC Integrated Epidemiology Unit and an author on the paper, added: “Work like this is really made possible as a result of the amazing properties presented by a study like Children of the 90s. Having biological samples for sequencing and rich life course data within a representative population sample is critical to allow new understanding and deep characterisation of important biological genetic effects like these.”

Professor Nic Timpson, Children of the 90s' Principal Investigator, and also one of the study’s authors, explained: “This work helps to recalibrate our understanding of the frequency and functional impact of rare MC4R mutations and will help to shape the future management of this important health factor – we extend our thanks to the participants of the Children of the 90s.”

Though the MC4R gene is a striking example, this is only one gene of many that affect our weight and there are likely to be further examples that emerge as genetic sequencing becomes more common.

In the longer term, knowledge of the brain pathways controlled by MC4R should help in the design of drugs that bypass the signalling blockade and help restore people to a healthy weight.

Reference
Wade KH et al. Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort. Nature Medicine; 27 May 2021

Adapted from a press release by the Wellcome-MRC Institute of Metabolic Science at the ̽��ֱ�� of Cambridge and the ̽��ֱ�� of Bristol

New research has found that one in every 340 people might carry a mutation in a single gene that makes them more likely to have a greater weight from early childhood and, by 18 years of age, they could be up to 30 pounds heavier with the excess weight likely to be mostly fat.

Our findings show that weight gain in childhood due to a single gene disorder is not uncommon. This should encourage a more compassionate and rational approach to overweight children and their families

Stephen O'Rahilly

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Weighing scales and tape measure

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